High-molecular derivative of 2-dimethylaminoethyl ester of p-butylaminobenzoic acid, method for preparing same and application thereof

ABSTRACT

The high-molecular derivative of 2-dimethylaminoethyl ester of p-butylaminobenzoic acid having the general formula   where x is the degree of substitution from 0.6 to 1.5 and n is the degree of polymerization from 30 to 120.

United States Patent 11 1 Pormale et al.

[ HIGH-MOLECULAR DERIVATIVE OF Z-DIMETHYLAMINOETHYL ESTER OFP-BUTYLANIINOBENZOIC ACID, METHOD FOR PREPARING SAME AND APPLICATIONTHEREOF [76] Inventors: Milda Yanovna Poi-male, ulitsa Suvorova 104, kv.10; Nadezhda Alexandrovna Kashkina, ulitsa Talsu 9/11, kv. 22; ElfridaIndrikovna Veinberg, ulitsa Volguntes, 78, kv. la; Arvid YanovichKalninsh, ulitsa Sverdlova 8, kv. 3; Janis Shusters, ulitsa Kveles 15,korpus 4, kv. Valdis Danielovich Mikazhans, ulitsa Marupes l7, kv.Indulis Valdovich Purvinsh, ulitsa Marupes, 17, kv 86a, all of Riga;Antons Petrovich Skutelis, Tuberkuleznaya bolnitsa Jugla", korpus 1, kv,7, Rizhsky raion, Stopinsky S/S, all of USSR [22] Filed: May 15, 1973[2]] Appl. No: 360,479

[ 1 Dec. 9, 1975 [52] U.S. Cl 260/214; 424/ [51] Int. Cl. C08B 3/00;A01N 9/00 [58] Field of Search 260/214, 231 CM, 232

[56] References Cited UNITED STATES PATENTS 2,3 [0,729 2/1943 Bley260/2l4 Primary Examiner-Ronald W. Griffin Attorney, Agent, orFirm-Haseltine, Lake & Waters 1 1 ABSTRACT The high-molecular derivativeof 2- dimethylaminoethyl ester of p-butylaminobenzoic acid having thegeneral formula ctr-r C,H,0, 0H rocH couNcn cu oco Q NHC.H,,

where x is the degree of substitution from 0.6 to 1.5 and n is thedegree of polymerization from 30 to 120.

6 Claims, N0 Drawings butylaminobenzoic acid in an aqueous medium at atemperature from 40 to 45C with subsequent isolation of the end productfrom the obtained solution.

The medicinal preparation of local anesthetic action contains an activeprinciple which is the high-molecular derivative of Z-dimethylaminoethylester of pbutylaminobenzoic acid, in combination with distilled water.

The present invention relates to a novel substance, viz., high-molecularderivative of Z-dimethylaminoethyl ester of p-butylaminobenzoic acid, toa method for preparing same and application thereof.

The novel substance has the following general formula n where x is thedegree of substitution from 0.6 to 1.5, and n is the degree ofpolymerization from 30 to 120.

The said compound is a white or slightly yellow amorphous hygroscopicsubstance readily soluble in water, insoluble in non-polar solvents,decomposing when exposed to the action of alkali.

The said high-molecular derivative of 2-dimethylaminoethyl ester ofp-butylaminobenzoic acid has biological activity and can be used inmedicine as an active principle in local anesthetics.

According to the invention, the method for preparing the high-molecularderivative of Z-dimethylaminoethyl ester of p-butylaminobenzoic acidconsists in the interaction between cellulosoglycolic acid andZdimethylaminoethyl ester of p-butylaminobenzoic acid in an aqueousmedium at a temperature 4045C with subsequent isolation of the mainproduct from the obtained solution.

As cellulosoglycolic acid reacts with Z-dimethylaminoethyl ester ofp-butylaminobenzoic acid, the hydrogen atom of the cellulosoglycolicacid accepts the unshared electron pair of the nitrogen atom belongingto the amino group in the lateral aliphatic chain of the molecule ofZ-dimethylaminoethyl ester of pbutylaminobenzoic acid, and the hydrogenatom is thus split off. The nitrogen-containing group gets positivelycharged.

In order to ensure high quality of the product, the process ofinteraction between cellulosoglycolic acid and Z-dimethylaminoethylester of p-butylaminobenzoic acid should be carried out at equimolecularratios, calculating with reference to the carboxyl groups of celluloseand amino groups of the aliphatic chain of the molecule of2-dimethylaminoethyl ester of pbutylaminobenzoic acid.

The process for preparing the high-molecular derivative ofZ-dimethylaminoethyl ester of p-butalaminobenzoic acid can be effectedwith excess quantities of 2- dimethylaminoethyl ester ofp-butylaminobenzoic acid with subsequent removal of the excess of thesaid ester by washing with acetone or ethyl alcohol during precipitationof the main product.

Sterile powder of the end product is prepared by lyophilic drying of theobtained solution.

As it has already been said, the high-molecular derivative of2-dimethylaminoethyl ester of pbutylaminobenzoic acid is the activeprinciple of a local anesthetic used in ophthalmological andotorhinolaryngological practice, in peridural anesthesia.

The proposed new preparation of local anesthetic action is used as asolution of the active principle, the high-molecular derivative of2-dimethylaminoethyl ester of p-butylaminobenzoic acid in distilledwater.

It is recommended that use be made of aqueous solutions having theconcentration of the active principle of 0.16 4.48 percent by weight.

With respect to the mechanism of its action, the proposed preparationdoes not differ from dicain (Tetracaim' hydrochloridum or Pantocain),but has a more pronounced and prolonged surface anesthetic effect.Furthermore, the new preparation is less toxic than dicain. Thecomparative characteristics of the local anesthetic action of theproposed preparation and dicain were studied by the Biilbrin and Wajdamethod on guinea pigs, into whose conjunctiva] sacs one drop of theproposed preparation and dicain were instilled in 4-6 variousconcentrations from 1.04 to 8.3 mmole/- liter. The effectiveness of thesurface anesthesia was estimated at 5-minute intervals until thesensitivity of the cornea was completely restored, as proved by all fivetouch test. Each concentration was tested on six animals, which wasessential for the judgement on the dynamics of the effectiveness of thesurface anesthesia, as well as on the length of the anesthetic effect ofthe preparation.

For a better comparison of the activity by the Miller and Taintermethod, mean concentrations (EC of the preparation ensuring 50 percentanesthesia during the first 30-minute period following theadministration of the preparation were determined, and their activitywith respect to that of dicain in aqueous solution was assessed. Fromthe thus-obtained data, the relative ac tivity of the preparation wasdetermined (the activity of dicain in aqueous solution was assumed I).The ob tained data show that the preparation containing thehigh-molecular derivative of 2-dimethylaminoethyl ester ofp-butylaminobenzoic acid is 2.1 times more effective than dicain withrespect to its surface anesthetic effect on the cornea of the eye inguinea pigs. With respect to the length of the permeation anestheticeffect, the proposed preparation is 1.5 2 times as superior as thecorresponding equimolar solutions of dicain.

The permeation (surface) anesthesia was compared by the Rnier method onrabbits, into the conjunctiva] sacs of which 2 drops of the proposedpreparation and dicain in seven various concentrations from 1.0 to 7.0mmole/liter were instilled. The average Rnier index was found from theobtained results, with the reliable limits for each test concentrationat p 0.05. Moreover, the length of the anesthetic effect on the corneawas assessed by continuing the determination of the Rnier index at5-minute intervals until the sensitivity of the cornea was completelyrestored as proved by the winking reflex to the first touch by a hair.

Each concentration was tested on five animals, and the response indicesduring l hour were summerized for each animal. It has been found thatwith respect to the surface anesthetic effect, the proposed preparationcontaining the high-molecular derivative of 2-dimethylaminoethyl esterof p-butylaminobenzoic acid is l .5 times more effective than dicain.

The study of acute toxicity was carried out on 108 albino mice (bothmales and females) with intraperitoneal administration of thepreparation. Each dose was given to a group of animals consisting of6-12 mice. The determination of acute toxicity of the preparation wasdone graphically by the Litchfield and Wilcoxon method on punched cardsby calculating the mean values with their reliable limits at P 0.05. Theprocessing of the obtained results has shown that the proposedpreparation is 1.3 times less toxic than dicain.

The range of the therapeutic action of the proposed preparation used forsurface anesthesia is 2.6 times wider than that of dicain.

1n ophthalmological practice, during extraction of foreign objects andvarious other surgical interventions on the eye, the preparationcontaining the highmolecular derivative of Z-dimethylaminoethyl ester ofp-butylaminobenzoic acid is given in doses of 2-3 drops of a 0.40-4.48percent solution.

In otorhinolaryngological practice, in some operative interventions(puncture of the sinus, adenotomy, conchotomy, operation on the middleear) the proposed preparation is used in the following doses: l-2 ml of1.0 2.24 percent solution.

For the peridural anesthesia, the following doses of the proposedpreparation are used: -20 ml of a 0.48 percent solution.

The greatest doses of the proposed preparation for adults: in anesthesiaof the upper respiratory ducts 0.14 0.18 g (single dose); in periduralanesthesia, 0.1 13-0150 g (single dose).

The contraindications for use are the same as with dicain.

The method for preparing the high-molecular derivative ofZ-dimethylaminoethyl ester of p-butylaminobenzoic acid, which is anactive principle of a local anesthetic, is effected as follows.

The reaction of interaction between cellulosoglycolic acid and2-dimethylamoniethyl ester of pbutylaminobenzoic acid is carried out inan aqueous medium, in which cellulosoglycolic acid is dissolved, while2-dimethylaminoethyl ester of p-butylaminobenzoic acid remainsundissolved.

The process is effected at a temperature of 4050C with intense stirring.The completeness of the process is controlled by determining the pH ofthe medium (6.5 7.0). As soon as the reaction has been completed, theprepared solution is separated from mechanical admixtures on a filterand dried lyophilically. 1f 2-dimethylaminoethyl ester ofp-butylaminobenzoic acid is taken in excess, the high-molecularderivative of 2- dimethylaminoethyl ester of p-butylaminobenzoic acidobtained in the reaction is precipitated by acetone or ethyl alcoholtaken in a quantity 5-10 times exceeding the volume of the startingsolution.

The yield of the end product is 72.0 98.2 percent by weight.

For a better understanding of the invention, the following examples ofits practical embodiment are given by way of illustration.

EXAMPLE 1 10 g of cellulose are treated with 100 ml of a 30 percentsolution of sodium hydroxide and 4.5 g of H 0 (15 ml of a 30 percentsolution) at a temperature of 35C for 1 hour. Alkalicellulose is treatedon a press, until its weight is three times that of the starting weightof the polymer, then ground, and kept at a temperature of 45C for 3hours. Alkalicellulose is then transferred into a threenecked flaskprovided with a reflux condenser, a stirrer and a thermometer, 140 ml ofisopropyl alcohol are added and then, at a temperature of 5060C, 12 g ofcrystalline monochloroacetic acid are added gradually with stirring. Thereaction is continued for 4-6 hours.

The thus obtained product is separated from the liquid phase and mixedwith a percent ethyl alcohol. A 30 percent solution of acetic acid isthen added to neutralize excess alkali. The product is washed with a 70percent ethyl alcohol to neutral reaction and reprecipitated two timeswith another washing with ethyl alcohol to remove possible admixtures.The thus obtained carboxymethylcellulose has the degree of substitution0.99 and the degree of polymerization l 15. The yield is 12.0 g (whichis 92 percent by weight of theory).

10 g of the product are solved in 200 ml of water and the solution ispassed through a cation exchanger (the H-form, the volumetric capacity,4.7 mg-equiv. per gram).

The COOH group content of cellulose is determined by potentiometrictitration and by drying a sample of cellulose to constant weight.

To ml ofa 5 percent solution of cellulosoglycolic acid are added 6.1 l gof Z-dimethylaminoethyl ester of p-butylaminobenzoic acid, and thecomponents are mixed for 30 minutes at a temperatures of 45C and the pHof the medium of 6.8. The thus prepared solution is then passed througha filter and dried lyophilically.

The yield of the end product is 1 1.1 g.

Calculated, from the formula (in percent by weight): N, 5.78 Found (inpercent by weight): N, 5.59; 5.66.

EXAMPLE 2 10 g of carboxymethylcellulose (the degree of substitution0.80 and the degree of polymerization 500) are mixed with 100 ml ofwater, and 2 ml of a 30 percent solution by hydrogen peroxide are added.The mixture is kept at a temperature of 45C for 2-3 hours, then passedthrough a filter and a cation-exchanger in the H-form. The preparedcelluloseglycolic acid has the: degree of polymerization of 76.

To 100 ml of a 5 percent solution of celluloseglycolic acid are added5.1 g of Z-dimethylaminoethyl ester of p-butylaminobenzoic acid. Theprocess is conducted at a temperature of 50C for 30 minutes until the pHof the solution is 6.6 6.8. The prepared solution is filtered and driedby lyophilization. The yield of the end product is 9.80 g which is 97percent by weight of theory.

Calculated, in percent: N 5.34; Z-dimethylaminoethyl ester ofp-butylaminobenzoic acid 50.5. Found, in percent: N 5.26;Z-dimethylaminoethyl ester of p butylaminobenzoic acid 49.7.

EXAMPLE 3 To 100 ml of a 5 percent aqueous solution of cellulosoglycolicacid prepared by the process described in Example 2 (the degree ofsubstitution 0.80, and the degree of polymerization 76) are added 6.0 gof 2- dimethylaminoethyl ester of p-butylaminobenzoic acid. Thecomponents are mixed at a temperature of 40C eral formula 3 1" c,H,0, oHmcn, OH. I cH,cH,oco NHQHJA,

where x is the degree of substitution from 0.6 to. 1.5, and n is thedegree of polymerization from 30 to I20.

2. A method for preparing a high-molecular derivative ofZ-dimethylaminoethyl ester of p-butylaminobenzoic acid having thegeneral formula where x is the degree of substitution from 0.6 to 1.5and n is the degree of polymerization from 30 to I20, consisting in theinteraction between cellulosoglycolic acid and Z-dimethylaminoethylester of p-butylaminobenzoic acid in an aqueous medium at a temperaturefrom 40 to 45C, with subsequent isolation of the end product from theobtained solution.

3. A method according to claim 2, in which 2-dimethylaminoethyl ester ofp-butylaminobenzoic acid and cellulosoglycolic acid are taken inequimolecular quantities.

4. A method according to claim 2, in which the end product is isolatedby precipitation with acetone.

5. A method according to claim 2, in which the end product is isolatedby precipitation with ethyl alcohol.

6. A method according to claim 2, in which the end product is isolatedby lyophilic drying of the obtained solution.

t t t

1. A HIGH-MOLECULAR DERIVATIVE OF 2-DIMETHYLAMINOETHYL ESTER OFP-BUTYLAMINOBENZOIC ACID HAVING THE GENERAL FORMULA
 2. A method forpreparing a high-molecular derivative of 2-dimethylaminoethyl ester ofp-butylaminobenzoic acid having the general formula
 3. A methodaccording to claim 2, in which 2-dimethylaminoethyl ester ofp-butylaminobenzoic acid and cellulosoglycolic acid are taken inequimolecular quantities.
 4. A method according to claim 2, in which theend product is isolated by precipitation with acetone.
 5. A methodaccording to claim 2, in which the end product is isolated byprecipitation with ethyl alcohol.
 6. A method according to claim 2, inwhich the end product is isolated by lyophilic drying of the obtainedsolution.